Method for enhancing the bioavailability of ospemifene

ABSTRACT

This invention relates to a method for enhancing the bioavailability of a therapeutically active compound of the formula (I) 
                         
or a geometric isomer, a stereoisomer, a pharmaceutically acceptable salt, an ester thereof or a metabolite thereof, wherein said compound is administered orally to the individual in connection with the intake of food.

FIELD OF THE INVENTION

This invention relates to a method for enhancing the bioavailability ofospemifene and closely related compounds by oral administering of saidcompounds in connection with food intake.

BACKGROUND OF THE INVENTION

The publications and other materials used herein to illuminate thebackground of the invention, and in particular, cases to provideadditional details respecting the practice, are incorporated byreference.

“SERM”s (selective estrogen receptor modulators) have both estrogen-likeand antiestrogenic properties (Kauffman & Bryant, 1995). The effects maybe tissue-specific as in the case of tamoxifen and toremifene which haveestrogen-like effects in the bone, partial estrogen-like effect in theuterus and liver, and pure antiestrogenic effect in breast cancer.Raloxifene and droloxifen are similar to tamoxifen and toremifene,except that their antiestrogenic properties dominate. Based on thepublished information, many SERMs are more likely to cause menopausalsymptoms than to prevent them. They have, however, other importantbenefits in elderly women: they decrease total and LDL cholesterol, thusdeminishing the risk of cardiovascular diseases, and they may preventosteoporosis and inhibit breast cancer growth in postmenopausal women.There are also almost pure antiestrogens under development.

Ospemifene is the Z-isomer of the compound of formula (I)

is one of the main metabolites of toremifene, and is known to be anestrogen agonist and antagonist (Kangas, 1990; International patentpublications WO 96/07402 and WO 97/32574). The compound is also called(deaminohydroxy)toremifene and is also known under the code FC-1271a.

Ospemifene has relatively weak estrogenic and antiestrogenic effects inthe classical hormonal tests (Kangas, 1990). It has anti-osteoporosisactions and it decreases total and LDL cholesterol levels in bothexperimental models and in human volunteers (International patentpublications WO 96/07402 and WO 97/32574). It also has antitumoractivity in an early stage of breast cancer development in an animalbreast cancer model. Ospemifene is also the first SERM which has beenshown to have beneficial effects in climacteric syndromes in healthywomen. The use of ospemifene for the treatment of certain climactericdisorders in postmenopausal women, namely vaginal dryness and sexualdysfunction, is disclosed in WO 02/07718. The published patentapplication WO 03/103649 describes the use of ospemifene for inhibitionof atrophy and for the treatment or prevention of atrophy-relateddiseases or disorders in women, especially in women during or after themenopause. A particular form of atrophy to be inhibited is urogenitalatrophy, which can be divided in two subgroups: urinary symptoms andvaginal symptoms.

Ospemifene is a highly lipophilic compound. Although ospemifene has anexcellent tolerability, a problem is the low aqueous solubility andrather low bioavailability. Therefore, when administered orally, therecommended daily dose is about 60 mg or more.

There is a great need for providing administering methods resulting inimproved bioavailability of ospemifene, and therefore the effect of foodintake on ospemifene was studied.

OBJECT AND SUMMARY OF THE INVENTION

An object of the present invention is to provide an improved oral methodof administering ospemifene, where the bioavailability of the drug isessentially increased.

Thus, the invention concerns a method for enhancing the bioavailabilityof a compound of the (I)

or a geometric isomer, a stereoisomer, a pharmaceutically acceptablesalt, an ester thereof or a metabolite thereof, wherein said compound isadministered to the individual in connection with the intake of food.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the mean serum concentration in male individuals (n=24) ofospemifene versus time following the administration of 60 mg ospemifenetablet in fasted condition (open circles) and after a high caloric,high-fat meal (filled circles).

FIG. 2 shows the mean serum concentration in male individuals (n=12) ofospemifene versus time following the administration of 60 mg ospemifenetablet in fasted condition (open circles); after a high caloric,high-fat meal (filled circles) and after a low caloric, low-fat meal(stars).

FIG. 3 shows the mean serum concentration in male individuals (n=12) ofthe ospemifene metabolite 4-hydroxy-ospemifene versus time following theadministration of 60 mg ospemifene tablet in fasted condition (opentriangles); after a high caloric, high-fat meal (filled triangles) andafter a low caloric, low-fat meal (crosses).

DETAILED DESCRIPTION OF THE INVENTION

Although it is previously known that certain lipophilic drugs maybenefit from administering the drug in connection with food intake, thestrength of the effect of food intake upon the ospemifenebioavailability obtained in the present investigations was verysurprising. Particularly compared to the behaviour of other SERMs, thefood effect on ospemifene is remarkable. It was found (Anttila M., 1997)that the intake of food did not have any positive effect on thebioavailability of toremifene, which like ospemifene also has a lowaqueous solubility. It was observed that food intake in fact retardedthe absorption of toremifene. It has also been reported that theadministration of raloxifene, another SERM, together with a standardizedhigh-fat meal increases the absorption of raloxifene slightly, but thatit does not lead to clinically meaningful changes in systemic exposure.While food intake causes only a 20% increase of raloxifene absorption,the effect on ospemifene absorption is a 2-3 fold increase.

The term “food” shall be understood to cover any edible foodstuff havinga nutritional value as an energy supplier. Thus the food can be solid,semisolid or liquid substance comprising one or more of the basicingredients carbohydrates, fats and proteins.

Surprisingly, a high percentage of fats or a high energy value in thefood intake is not crucial for obtaining a high bioavailability forospemifene. Neither is the amount of food intake crucial for thebeneficial effect.

It is believed that the secretion of bile acids may play an importantrole in the improved bioavailability, and therefore any foodstuff beingcapable of causing secretion of bile acids is expected to work.

The drug is considered to be administered in connection with the intakeof food if the drug is administered at a time point shortly before thestart of the food intake, during the food intake or in a relativelyshort time after the food intake is completed. A preferable time rangeis defined to begin 1 hour before starting the food intake and to end 2hours after starting the food intake. More preferably, the drug isadministered at a time point which is in the range defined to begin at atime point during the food intake and to end 1 hour after the foodintake was started. Most preferably, the drug is administered during thefood intake or at a time point which is no later than 0.5 hour afterstarting the food intake.

The method of enhancing the bioavailability of ospemifene and relatedcompounds according to this invention is particularly useful whentreating women during or after the menopause. However, the methodaccording to this invention is not restricted to women in this agegroup.

The term “metabolite” shall be understood to cover any ospemifene or(deaminohydroxy)toremifene metabolite already discovered or to bediscovered. As examples of such metabolites can be mentioned theoxidation metabolites mentioned in Kangas (1990) on page 9 (TORE VI,TORE VII, TORE XVIII, TORE VIII, TORE XIII), especially TORE VI and TOREXVIII, and other metabolites of the compound. The most importantmetabolite of ospemifene 4-hydroxyospemifene, which has the formula

The use of mixtures of isomers of compound (I) shall also be included inthis invention.

The method of enhancing bioavailability is useful in any application ofospemifene, especially when the compound is used for treatment orprevention of osteoporosis or for treatment or prevention of symptomsrelated to skin atrophy, or to epithelial or mucosal atrophy.

A particular form of atrophy which can be inhibited by administering ofospemifene is urogenital atrophy. Symptoms related to urogenital atrophycan be divided in two subgroups: urinary symptoms and vaginal symptoms.As examples of urinary symptoms can be mentioned micturation disorders,dysuria, hematuria, urinary frequency, sensation of urgency, urinarytract infections, urinary tract inflammation, nocturia, urinaryincontinence, urge incontinence and involuntary urinary leakage.

As examples of vaginal symptoms can be mentioned irritation, itching,burning, maladorous discharge, infection, leukorrhea, vulvar pruritus,feeling of pressure and postcoital bleeding.

According to previous data, the optimal clinical dose of ospemifene isexpected to be higher than 25 mg daily and lower than 100 mg daily. Aparticularly preferable daily dose has been suggested in the range 30 to90 mg. At the higher doses (100 and 200 mg daily), ospemifene showsproperties more similar to those of tamoxifen and toremifene. Due to theenhanced bioavailability according to the method of this invention, itcan be predicted that the same therapeutical effect can be achieved withdoses lower those recommended earlier.

The invention will be disclosed more in detail in the followingnon-restrictive Experimental Section.

Experimental Section

Two clinical studies were carried out in order to assess thebioavailability of ospemifene in healthy male subjects after intake ofhigh caloric content (860 kcal) and high-fat breakfast compared tobioavailability of ospemifene administered in fasted condition (studyA). In a separate study (study B), the bioavailability of ospemifeneafter intake of low caloric content (300 kcal), low-fat breakfast wasassessed and the results were compared to those obtained in study A(i.e. ospemifene bioavailability after intake of high caloric, high-fatbreakfast or after ospemifene administering in fasted condition).

Study A

In study A, 24 healthy male volunteers (mean age 23.8 years, mean BMI22.8 kg/m²) received single oral doses of 60 mg ospemifene, once underfed condition after consuming a standardised high-fat, high caloricbreakfast, and once after an overnight fast. Blood samples forpharmacokinetic assessments were drawn during 72 hours at each studyperiod. A washout period between the two treatments was at least 2weeks. The breakfast consisted of the following ingredients: two eggsfried in butter (50 g), two strips of bacon (34 g), two slices of toastwith butter (50 g), 60 g hash brown potatoes and 240 ml of whole milk(percentage of fat=3.5%). The meal provided approximately 150, 170 and540 kcal from protein, carbohydrate and fat, respectively.

Ospemifene Administration in Connection With High Caloric, High-Fat TestMeal:

Following an overnight fast of at least 10 hours at the study site, thesubjects were given the test meal described above 30 minutes beforeospemifene dosing (60 mg tablet). The meal had to be consumed over the30 minutes, immediately followed by administration of ospemifene.

Ospemifene Administration in Fasted Condition:

Following an overnight fast of at least 10 hours at the study site, thesubjects were given one ospemifene tablet (60 mg) with 240 ml of water.No food was allowed for at least 4 hours after the ospemifene dose.

Results from Study A

A substantial effect of food intake was observed on the bioavailabilityof ospemifene and its main metabolite 4-hydroxy-ospemifene. FIG. 1 showsthe mean serum concentration of ospemifene versus time following theadministration of 60 mg ospemifene tablet in fasted condition (opencircles) and after a high caloric, high-fat meal (filled circles). Theresults of this study showed clearly that the ospemifene bioavailabilitywas enhanced by concomitant ingestion of ospemifene and a meal.

Due to the surprising and promising results of this study it was decidedto carry out a second study (study B below) to find out the effect of alow caloric, low-fat meal on the bioavailability of ospemifene.

Study B

In study B, 12 healthy male volunteers (mean age 23.8 years, mean BMI22.3 kg/m²) of the 24 subjects in study A were subjected to ospemifeneadministering in combination with the intake of a low caloric, low-fatmeal. The results were compared to those obtained in study A for thesame individuals.

Ospemifene Administering in Connection with Low Caloric, Low-Fat Meal:

The composition of the light breakfast (approximately 300 kcal) was asfollows: two slices of toast with margarine (5 g, fat content 60%), 6slices (30 g) of cucumber, 240 ml skimmed (non-fat) milk and 100 mlorange juice. The test meal provided approximately 50, 180 and 70 kcalfrom protein, carbohydrate and fat, respectively.

Following an overnight fast of at least 10 hours at the study site, thesubjects were given the test meal described above 30 minutes beforeospemifene dosing (60 mg tablet). The meal had to be consumed over the30 minutes, immediately followed by administration of ospemifene.

Results from Study B

FIG. 2 shows the mean serum concentration of ospemifene versus timefollowing the administration of 60 mg ospemifene tablet in fastedcondition (open circles; data obtained from study A); after a highcaloric, high-fat meal (filled circles; data obtained from study A) andafter a low caloric, low-fat meal (stars). FIG. 3 shows the mean serumconcentration of the ospemifene metabolite 4-hydroxy-ospemifene versustime following the administration of 60 mg ospemifene tablet in fastedcondition (open triangles; data obtained from study A); after a highcaloric, high-fat meal (filled triangles; data obtained from study A)and after a low caloric, low-fat meal (crosses).

The results of this study showed clearly that the bioavailability ofospemifene was also enhanced by concomitant ingestion of ospemifene anda low caloric, low-fat meal. Although the fat content of the low-fatmeal was much lower than that of the high-fat meal, the bioavailabity ofospemifene was only slightly lower for the low-fat meal. Therefore itcan be concluded that the effect of food on the ospemifenebioavailability is not dependent on the fat content of the mealingested. Instead, stimulation of bile flow due to meal ingestion mayenhance the solubilisation of ospemifene.

It will be appreciated that the methods of the present invention can beincorporated in the form of a variety of embodiments, only a few ofwhich are disclosed herein. It will be apparent for the expert skilledin the field that other embodiments exist and do not depart from thespirit of the invention. Thus, the described embodiments areillustrative and should not be construed as restrictive.

BIBLIOGRAPHY

-   Anttila M. Effect of food on the pharmacokinetics of toremifene. Eur    J Cancer, 1997; 33, suppl 8: 1144, 1997.-   Kangas L. Biochemical and pharmacological effects of toremifene    metabolites. Cancer Chemother Pharmacol 27:8-12, 1990.-   Kauffman R F, Bryant H U. Selective estrogen receptor modulators.    Drug News Perspect 8: 531-539, 1995.

The invention claimed is:
 1. A method for treating one or more vaginalsymptoms of urogenital atrophy due to menopause with ospemifene, theimprovement comprising increasing ospemifene absorption by about 2-3fold by orally administering the ospemifene in connection with theintake of a meal, wherein the increase is as compared to theadministration of ospemifene in a fasted state.
 2. The method of claim1, wherein the meal comprises a high-fat, high-calorie meal.
 3. Themethod of claim 1, wherein the meal comprises a low-fat, low-caloriemeal.
 4. The method of claim 1, wherein peak ospemifene mean serumconcentration is reached in about 2-3 hours after administration.
 5. Themethod of claim 4, wherein the increase in peak mean serum concentrationis between 1 and 4 times greater as compared to said administration in afasted state.
 6. The method of claim 1, wherein the improvement furthercomprises instructing a patient that ospemifene should be taken withfood.
 7. A method for treating one or more vaginal symptoms ofurogenital atrophy due to menopause, comprising increasing the peak meanserum concentration of ospemifene by orally administering ospemifene inconnection with a meal, wherein the increase in peak mean serumconcentration of ospemifene is as compared to the administration in afasted state.
 8. The method of claim 7, wherein the increase is between1 and 4 times greater.
 9. The method of claim 7, wherein the mealcomprises a high-fat, high-calorie meal.
 10. The method of claim 7,wherein the meal comprises a low-fat, low-calorie meal.
 11. The methodof claim 7, wherein the peak ospemifene mean serum concentration isreached in about 2-3 hours after administration.
 12. The method of claim11, wherein ospemifene absorption increases by about 2-3 fold.
 13. Themethod of claim 7, further comprising instructing a patient thatospemifene should be taken with food.
 14. A method of treating one ormore vaginal symptoms of urogenital atrophy due to menopause, comprisingorally administering a therapeutically effective amount of ospemifene inconnection with a meal wherein the absorption of ospemifene is increasedby about 2-3 fold, wherein the increase is as compared to theadministration of ospemifene in a fasted state.
 15. The method of claim14, wherein the meal comprises a high-fat, high-calorie meal.
 16. Themethod of claim 14, wherein the meal comprises a low-fat, low-caloriemeal.
 17. The method of claim 14, wherein the peak ospemifene mean serumconcentration is reached in about 2-3 hours after administration. 18.The method of claim 17, wherein the increase in peak mean serumconcentration is about 1-4 times greater.
 19. The method of claim 14,further comprising instructing a patient that ospemifene should be takenwith food.
 20. A method for enhancing the absorption of orallyadministered ospemifene for the treatment of one or more symptoms ofmenopause, comprising administering said ospemifene in connection withthe intake of a meal, thereby increasing the absorption of ospemifene byabout 2-3 fold, wherein the increase is as compared to theadministration of ospemifene in a fasted state.
 21. The method of claim20, wherein the meal comprises a high-fat, high-calorie meal.
 22. Themethod of claim 20, wherein the meal comprises a low-fat, low-caloriemeal.
 23. The method of claim 20, wherein the peak ospemifene mean serumconcentration is reached in about 2-3 hours after administration. 24.The method of claim 23, wherein the increase in peak mean serumconcentration is about 1-4 times greater.
 25. The method of claim 20,further comprising instructing a patient that ospemifene should be takenwith food.
 26. A method for increasing the bioavailability of orallyadministered ospemifene, comprising orally administering ospemifene inconnection with a meal, thereby increasing the peak mean serumconcentration of ospemifene as compared to administration in a fastedstate.
 27. The method of claim 26, wherein the increase is between 1 and4 times greater.
 28. The method of claim 26, wherein the meal comprisesa high-fat, high-calorie meal.
 29. The method of claim 26, wherein themeal comprises a low-fat, low-calorie meal.
 30. The method of claim 26,wherein the peak mean serum concentration is reached in about 2-3 hoursafter administration.
 31. The method of claim 30, wherein ospemifeneabsorption increases by about 2-3 fold.
 32. The method of claim 26,further comprising instructing a patient that ospemifene should be takenwith food.